title: Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy.
abstract: Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.
authors.affiliation: Department of Microbiology & Immunology and 2 Department of Physiology and Cell Biology, University of Nevada-Reno School of Medicine, Reno, NV 89557.
authors.forename: Myriam N
authors.initials: MN
authors.lastname: Bouchlaka
authors.forename: Gail D
authors.initials: GD
authors.lastname: Sckisel
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.forename: Annie
authors.initials: A
authors.lastname: Mirsoian
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Zamora
authors.forename: Emanual
authors.initials: E
authors.lastname: Maverakis
authors.forename: Danice E C
authors.initials: DE
authors.lastname: Wilkins
authors.forename: Kory L
authors.initials: KL
authors.lastname: Alderson
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Hsiao
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.forename: Charles
authors.initials: C
authors.lastname: Hesdorffer
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.forename: Doug
authors.initials: D
authors.lastname: Redelman
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Taub
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000375:Aging / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D019013:CD40 Antigens / Q000276:immunology; D016207:Cytokines / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha